Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

The α- and β-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life. Reactivation of these genes may offer therapeutic approaches for the hemoglobinopathies, the most common single gene disorders. Here, we address mechanisms regulating the embryonically expressed α-like globin, termed ζ-globin. We show that in embryonic erythroid cells, the ζ-gene lies within a ~65 kb sub-TAD (topologically associating domain) of open, acetylated chromatin and interacts with the α-globin super-enhancer. By contrast, in adult erythroid cells, the ζ-gene is packaged within a small (~10 kb) sub-domain of hypoacetylated, facultative heterochromatin within the acetylated sub-TAD and that it no longer interacts with its enhancers. The ζ-gene can be partially re-activated by acetylation and inhibition of histone de-acetylases. In addition to suggesting therapies for severe α-thalassemia, these findings illustrate the general principles by which reactivation of developmental genes may rescue abnormalities arising from mutations in their adult paralogues.

Original publication

DOI

10.1038/s41467-021-24402-3

Type

Journal article

Journal

Nature communications

Publication Date

21/07/2021

Volume

12

Addresses

MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

Keywords

Chromatin, Erythroid Cells, Animals, Humans, Mice, DNA-Binding Proteins, Transcription Factors, Repressor Proteins, Gene Expression Regulation, Developmental, Gene Silencing, Acetylation, Enhancer Elements, Genetic, Transcriptional Activation, alpha-Globins, zeta-Globins, Histone Deacetylase Inhibitors